Progesterone containing oral dosage forms and kits

ABSTRACT

The present invention provides for progesterone containing pharmaceutical oral dosage forms, pharmaceutical kits, and related methods. In one embodiment, an oral dosage form formulated for on-going administration is provided. The oral dosage form includes an amount of progesterone and a pharmaceutically acceptable carrier. The oral dosage form is formulated such that upon single dose administration to a non-pregnant woman in follicular phase, the oral dosage form provides a serum progesterone C 24h  of at least 0.20 ng/mL.

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/204,562, filed Aug. 5, 2011, which is a continuation ofPCT/US2011/041123, filed on Jun. 20, 2011, which claims the benefit ofU.S. patent application Ser. No. 12/819,125, filed on Jun. 18, 2010,each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to progesterone compositions, oral dosageforms and associated methods. Accordingly, this invention involves thefields of chemistry, pharmaceutical sciences, medicine and other healthsciences.

BACKGROUND OF THE INVENTION

Progesterone (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involvedin the female menstrual cycle, pregnancy (supports gestation), andembryogenesis of humans and other species. Progesterone belongs to aclass of hormones called progestogens, and is the major naturallyoccurring human progestogen. Progesterone can be used alone, or incombination with estrogenic agents, to provide a hormonal state in womenthrough hypothalamic, pituitarian, and some endometrial effects toenable contraception and some non-contraception indications, such asendometriosis, regular menstrual cycles, improvement in acne,dysmenorrhea and premenstrual symptoms such as dysphoric disorder, alsoknown as PMDD, polycystic ovarian syndrome (PCOS), perimenopause,hirsutism (undesired body or facial hair growth). Although quiteeffective, oral hormonal contraceptive use is generally characterized bypoor adherence and relatively high discontinuation. The primaryobjective of contraception is to achieve an anovulatory state withacceptable menstrual cycle characteristics and side effect profile.

Progesterone's role in contraception is primarily through prevention ofovulation by suppressing follicle stimulating hormone (FSH) andluteinizing hormone (LH), preventing implantation of fertilized ovum bysuppressing endometrium development, and to thicken cervical mucusmaking sperm penetration difficult. Synthetic or natural estrogen, ifused in combination with a progestogen, provides better cycle controland prevents estrogen deficiency due to decreased secretion ofendogenous estrogen from the follicle. Estrogen inhibits FSH releasefrom the anterior pituitary to prevent selection of dominant follicle,to provide stability to endometrium, to decrease rate of breakthroughbleeding, to thin cervical mucus, and to increase expression ofprogesterone receptors.

Progestogen only pills (POPs) for oral contraception are typicallystarted on days 1 to 5 of the menstrual cycle and particularly suitedfor women who are smokers and over 35 years old, overweight or obese,over the age of 45, diabetic, prone to chloasmia, intolerant toestrogen, nursing mothers, prone to migraine with aura, and havehypertension. Currently, combination (progestogen plus estrogen) oralcontraceptive (COC) pills are most preferred due to reportedly morereliable efficacy if used as directed, they have better cycle controland are more forgiving with respect to missed dose related safetymargins associated with contraception failure. In contrast, commerciallyavailable progestogen-only oral contraceptives must be taken at nearlythe exact same time every day to reduce the risk of contraceptivefailure with “missed dose” related safety margin of only a few hours.

Orally-administered progesterone undergoes several successive metabolicsteps in the gut, intestinal wall, and liver. The first step is thecontact with intestine bacteria which has 5α reductase activity, thenwith the intestinal wall, predominantly the upper gastro-intestinal wallwhich has 5α-reductase activity and also initiates conjugation ofsteroids with glucuronic acid. The second step is the contact with liverenzymes after circulation in the portal vascular systems. Liver cells inwomen express mainly 5α-reductase, 3α and 20α-hydroxylase activities.3α-OH-5α-pregnan-20-one is known as allopregnanolone and3α-OH-5α-pregnan-20-one is known as pregnanolone. Both of themetabolites can be collectively addressed as “pregnane” metabolites.Pregnane metabolites are neurosteroids and are active agonists on theGamma Amino Butyric Acid-A (GABA_(A)) receptor unlike progesterone perse. High doses of GABA_(A) receptor agonists such as pregnanemetabolites induce dizziness, sedation, hypnosis, and anxiolysis, andare antiepileptic. Therefore, reduced level of pregnane metabolitesprovides acceptable progesterone therapy without significant adverseevents such as sedation, dizziness and hypnosis.

Synthetic combination oral contraceptives also have highercardiovascular risk such as ischemic stroke, venous thromboembolism(VTE), myocardial infarction, arterial hypertension. It has beensuggested that COC's may contribute to the risk of breast cancer in awoman. These side effects and increased risks are associated with,progestin and/or estrogen, its relative doses, or the recommended dosingregimen. Overall, the lack of high selectivity/specificity of syntheticprogestins to progesterone receptors, estrogenic action and/oranti-estrogenic action, antimineralocorticoid activity, androgenicaction and/or anti androgenic action, appear to be associated withvarying intensities of the side effects. Unlike some syntheticprogestins like gestodene, levonorgesterol, etc. natural progesteronehas low binding affinities to human sex hormone binding globulin (SHBG).Progestins having antiandrogenicity effects could result in loss oflibido and compromised sexual health. This can be particularly true whenthey are combined with ethinyl estradiol. This effect is primarily dueto androgen insufficiency through direct inhibition of androgenproduction in the ovaries and by a marked increase in the hepaticsynthesis of SHBG, which is known to bind to circulating testosteronemaking it less bioavailable. Increases in SHBG values as high as 400%have been reported in users of ethinyl estradiol based combination oralcontraception as compared to women who never used combination oralcontraception.

The delivery of progesterone via oral route in a suitable way forcontraception and non-contraception use still remains a challenge givenits extensive metabolism to neurosteroids. With this in mind, researchcontinues to develop natural progesterone oral dosage forms that can beused to effectively provide contraceptive and non-contraceptive activitywithout having the negative side-effects associated with syntheticprogestins.

Currently, ethinyl estradiol (EE) is the most utilized estrogen in acombination oral pill with androgenic progestin such as levonorgestrel(e.g. Lybrel®) or anti-androgenic progestin such as drosperinone (e.g.Yaz® and Yasmin®). Estrone producing bioidentical 17-estradiol or itsester prodrug, estradiol valerate, is also commonly combined withprogestins in combination oral pills, e.g. Natazia® withdienogest/estradiol valerate, Zoely® with nomegestrol acetate with17-estradiol), and presumably have less hepatic effect compared to EEcontaining combinations. However, their use in combination may providecycle management challenges that need to be offset by proper choice ofprogestin, balance of progestin to estrogen, and multitude of dosingregimens for acceptable cycle control. A combination of estradiol andnorethindrone acetate is available for non-contraception treatment ofmoderate to severe vasomotor symptoms associated with menopause,prevention of postmenopausal osteoporosis, and treatment of moderate tosevere symptoms of vulvar and vaginal atrophy associated with menopause.

Currently, the only known POP contraceptive pills are in the form ofanti-androgenic desogestrel sold outside the U.S. as Cerazette® with a12 hour “missed dose” related safety margin to prevent contraceptionfailure and androgenic norethindrone sold as Micronor® in US with a 3hour “missed dose” related safety margin for contraception failure, orandrogenic levonorgestrel sold as Microlut®. Most available combinationpill contain anti-androgenic progestins such as drospirenone anddinogest, or androgenic levogersterol, and norethindrone. Normegesterolacetate (NOMAC), a non-androgenic and non-anti-androgenic progestin witha long half-life is devoid of anti-mineralocorticoid activity, which iscritical to manage metabolic side effects. It is also known thatprogestins with stronger androgenic activity have a stronger negativeimpact on lipid metabolism.

The sub-optimal half-life of synthetic androgenic or antiandrogenicprogestins present challenges w.r.t. to pill amenorrhea due to very longhalf-life in women who desire to bleed at least few times a year toascertain their reproductive health and time to reversibility (e.g. ˜7days with drosperinone-containg pills) in case of contraceptioncessation and wanting to become pregnant without risking progestineffects on the fetus. While shorter half progestins have favorable pillamenorrhea and reversibility profile they also result in a shortermissed dose safety margin of 3 hr and lower efficacy due to loweranovulation rates (˜50%) such as with norethindrone.

SUMMARY OF THE INVENTION

The present invention provides for progesterone containingpharmaceutical oral dosage forms, pharmaceutical kits, and relatedmethods. In one embodiment, an oral dosage form formulated for on-goingadministration is provided. The oral dosage form can include an amountof progesterone and a pharmaceutically acceptable carrier. The oraldosage form is formulated such that upon single dose administration to anon-pregnant woman in follicular phase, the oral dosage form provides aserum progesterone C_(24h) of at least 0.20 ng/mL.

In another embodiment, an oral dosage form for ongoing administration isprovided that includes an amount of progesterone and a pharmaceuticalacceptable release modulator. The oral dosage form can be formulatedsuch that wherein upon dissolution of the oral dosage using a USP Type-1dissolution apparatus in 900 mL of de-ionized water with 2.0% (w/v) ofsodium lauryl sulfate at 100 rpm, less than 10 wt % of the progesteroneis released from the dosage form after about 1 hour, 50 wt % or less ofthe progesterone is released in the first 6 hours and at least 70 wt %of the progesterone is released within 12 hours.

In a further embodiment, a pharmaceutical kit is provided. The kit caninclude a plurality of doses of a progesterone-containing oral dosageform and optionally a placebo dose of an oral dosage form. The pluralityof progesterone-containing oral dosage forms can include oral dosageforms having different doses of progesterone. The kit can be such thatupon single dose administration of one of the progesterone-containingoral dosage forms to a non-pregnant woman in follicular phase themenstruation cycle, the progesterone-containing oral dosage formprovides a ratio of increased serum progesterone AUC₁₂₋₂₄ (ng*h/mL) toadministered dose (mg) is at least 0.005 (ng*h/ml)/mg and does notexceed about 0.03 (ng*h/ml)/mg. Furthermore, such a kit may include aset of instructions on dosing or other information regarding aprogesterone regimen using the included progesterone-containing oraldosage form along with any optional placebo doses.

In another embodiment, the oral dosage forms set forth in the aboveembodiments can include an estrogenic compound. In still a furtherembodiment, the oral dosage form is formulated such that upon attainmentof steady state blood levels to a non-pregnant woman, the oral dosageform provides a serum progesterone C_(24h) of at least 0.35 ng/mL

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows simulated steady state concentrations of progesterone uponadministration of dosage forms 8, 11 and 43 with 400 mg progesterone.

FIG. 2 shows simulated steady state concentrations of progesteronemetabolites in vivo upon administration of dosage forms 8, 11 and 43,each dosage form containing 400 mg progesterone. Among the dosage formsadministered dosage form 43 gives very high concentrations ofmetabolites while dosage form 11 gives very low levels of metabolites.Dosage form 8 maintains acceptable/desirable levels of metabolites whilemaintaining safe and effective concentrations of progesterone.

FIG. 3 shows simulated steady state concentrations of progesterone invivo upon administration of different dosage forms 8, 11 and 43, eachdosage form containing 400 mg progesterone. In particular, the steadystate concentrations are shown when one of the dose administrations isdelayed by 12 hours (i.e. at 108 hrs instead of 96 hrs). Among thedosage forms administered, dosage forms 11 and 43 have levels that dropbelow therapeutically effective concentrations when dose is delayed. Incontrast, dosage form 8 maintains effective levels of progesteronethereby providing for significant window of safety and efficacy.

FIG. 4 shows comparative release profiles of oral dosage forms 9, 16,26, and 43 upon placement of the oral dosage in a USP Type-1 dissolutionapparatus in 900 mL of de-ionized water with 2.0% (w/v) of sodium laurylsulfate at 100 rpm.

FIG. 5 shows a plot of the reversibility of contraception based on sevenhalf-lives of progestogen in various commercially availablecontraceptive dosage form/kits containing progestins as well as that foran embodiment of the present invention of progesterone containingcontraceptive dosage form/kit, following cessation of administration ofthe respective dosages.

DETAILED DESCRIPTION

Before the present oral dosage forms and methods for the delivery anduse of progesterone are disclosed and described, it is to be understoodthat this invention is not limited to the particular process steps andmaterials disclosed herein, but is extended to equivalents thereof, aswould be recognized by those ordinarily skilled in the relevant arts. Itshould also be understood that terminology employed herein is used forthe purpose of describing particular embodiments only and is notintended to be limiting.

It should be noted that, the singular forms “a,” “an,” and, “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to “an excipient” includes reference to oneor more of such excipients, and reference to “the carrier” includesreference to one or more of such carriers.

DEFINITIONS

As used herein, “drug,” “active agent,” “bioactive agent,”“pharmaceutically active agent,” “therapeutically active agent” and“pharmaceutical,” may be used interchangeably to refer to an agent orsubstance that has measurable specified or selected physiologic activitywhen administered to a subject in a significant or effective amount. Itis to be understood that the term “drug” is expressly encompassed by thepresent definition as many drugs and prodrugs are known to have specificphysiologic activities. These terms of art are well-known in thepharmaceutical and medicinal arts. Further, when these terms are used,or when a particular active agent is specifically identified by name orcategory, it is understood that such recitation is intended to includethe active agent per se, as well as pharmaceutically acceptable salts,esters or compounds significantly related thereto, including withoutlimitation, prodrugs, active metabolites, isomers, and the like, unlessthe context or scientific principles clearly indicate otherwise.

As used herein, the term “treatment” when used in conjunction with theadministration of progesterone, refers to the administration ofprogesterone to subjects who are either asymptomatic or symptomatic. Inother words, “treatment” can be to reduce, ameliorate, or eliminatesymptoms associated with a condition or it can be prophylactictreatment, i.e. to prevent or reduce the occurrence or severity of thesymptoms. Such prophylactic treatment can also be referred to asprevention of the condition.

As used herein, “treatment” also refers to a change/alteration that isbrought about in a subject's typical physiological processes followingadministration of a drug in a given dosage form, as in case for example,contraception provided by the single or multiple dose administration ofthe current invention's dosage forms which result in inhibiting theovulation phase of the typical menstrual cycle.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Furthermore, the term “dosageform” can include one or more formulation(s) or composition(s) providedin a format for administration to a subject. When any of the above termsis modified by the term “oral” such terms refer to compositions,formulations, or dosage forms formulated and intended for oraladministration to subjects.

As used herein, “carrier” or “pharmaceutically acceptable carrier”refers to a substance with which a drug may be combined to achieve aspecific dosage formulation or oral dosage form for delivery to asubject. In the some aspects of the present invention, the carriers usedmay or may not enhance drug delivery. Further, the carrier, or at leasta portion thereof must be suitable for administration into a subjectalong with the drug.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention. In onespecific aspect, a subject is a human. In another aspect, the subject isa female. In one embodiment, the subject can be a non-pregnant female orwoman. In another embodiment the subject can be a non-pregnant woman inthe follicular phase of the menstruation cycle.

For the purposes of the present disclosure, the term a single“menstruation cycle” has a typical duration of about 28 days. The term“follicular phase” refers to the initial phase of a woman's menstruationcycle which typically has a duration of from about day 1 to about day 10from the start of the menses, in a normal menstruating women, this phaseoccurs before ovulation. The term “luteal phase” refers to the laterphase of a woman's menstrual cycle which typically has a duration offrom about 14-28 days, in normal menstruating women, this phase startsfrom about ovulation to the next menses.

The term “oral administration” represents any method of administrationin which an active agent can be administered by swallowing, chewing, orsucking or drinking an oral dosage form. Such solid or liquid oraldosage forms are traditionally intended to substantially release and ordeliver the active agent in the gastrointestinal tract beyond the mouthand/or buccal cavity. Examples of solid dosage forms includeconventional tablets, multi-layer tablets, capsules, caplets, etc.,which do not substantially release the drug in the mouth or in the oralcavity.

As used herein, the terms “release” and “release rate,” are usedinterchangeably to refer to the discharge or liberation of a substance,including without limitation a drug, from the dosage form into asurrounding environment such as an aqueous medium either in vitro or invivo.

As described herein, “Saccadic Eye Velocity” (SEV), a psychometricmethod, can be measured using the following test method: a subject'shead is restrained and an light emitting object placed in front of eyesis moved to a certain angle either to left or right in front of eyes andthe speed with which the eye ball moves to follow the light is measuredas a function of time.

As used herein, the term “substantially free of” as it refers to thepresence or lack of a particular composition or ingredient or componentin a given formulation or oral dosage form refers to the complete ornear complete absence of the ingredient from the formulation such thatthe ingredient, if present, forms only a minor component or impurity ofthe formulation. For example, a composition that is substantially freeof edible oils may contain a small amount of edible oil impurities thatmay be present in commercially available surfactants or othercommercially available non-edible oil compositions. In one aspect, aformulation that is substantially free of edible oils could have lessthan 10 wt % of edible oils present in the formulation. In anotheraspect, a formulation that is substantially free of oils could have lessthan 5 wt % of edible oils present in the formulation. In yet anotheraspect, a formulation that is substantially free of edible oils couldhave less than 2.5 wt % of edible oils present in the formulation.

As used herein, “edible oil” is any oil that can be safely consumed by amammal. These oils will generally be selected from those oils generallyregarded as safe for pharmaceutical or culinary use. Suitable edibleoils for the present invention include, but are not limited to,safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, sesameoil, olive oil, cottonseed oil, flaxseed oil, menhaden oil. For thepurpose of this invention, the primary characteristic of an “edible oil”is that they are triglycerides of long chain fatty acids with carbonchain length of 12 to 18 and do not include oils which have carbon chainlength greater than 20 such as oils containing omega fatty acids,example fish oil, flax seed oil, algae oil and the like.

The terms “release modifying agent”, “release modulator”, and “releasemodifiers” are used interchangeably and refer to pharmaceuticallyacceptable agents or devices that are able to alter, delay, target,increase or decrease, or otherwise customize, the release rates of atleast one of the contents of the compositions or dosage form, whenexposed to an aqueous use environment. With this in mind, a “hydrophilicrelease modulator” is a release modulator that has a tendency to bind orabsorb water. This binding or absorption can result in swelling and/orthe formation of reversible gels that can control the release of activeagents in a dosage form. Similarly, a “lipophilic release modulator” isa release modulator that has an affinity for fats and/or oils. Withinbeing limited by theory, some lipophilic release modulators can modifyrelease by forming films or by slowing the erosion or digestion of anoral dosage form. A “lipidic lipophilic modulator” is a lipophilicrelease modulator that is an oil or fatty substance. Accordingly, a“non-lipidic lipophilic release modulator” is a lipophilic releasemodulator that is not an oil or fatty substance.

As used herein, the term “placebo” used to describe a dose or oraldosage form refers to a dose or oral dosage form that includes noprogesterone. While the placebo oral dosage form are free ofprogesterone, such oral dosage forms may contain other active agentssuch as estrogenic agents, androgenic agents, vitamins, folic acid, painrelievers, etc.

By “osmotic agent” is meant any agent that creates a driving force fortransport of water from the environment of use into the core of thedosage form.

As used herein, the terms “progesterone,” “bio-identical progesterone”or “natural progesterone” are used interchangeably and refer toprogesterone that has molecular and chemical properties that are thesame as those of the progesterone that is naturally present in the humanbody, it is generally known to those skilled in art as moleculeidentified by CAS No. 57-83-0.

As used herein the term “bio-identical estrogenic agent” refers to anestrogenic agent whose molecular and chemical properties is identical tothat of the estrogen present in the human body, it is generally known tothose skilled in art as estradiol molecule identified by CAS No.50-28-2. Bio-identical estrogenic agents can be obtained from naturalsources or by chemical synthesis.

As used herein, the phrase “ongoing administration” refers toadministration of an oral dosage form for a period of 10 or moreconsecutive days.

Steady state concentration, C_(ss), corresponds to the state ofequilibrium obtained at the end of a certain number of administrations.To obtain an increase in the plasma concentration with repeatedadministrations, it is necessary that a residual concentration persistsat the time of the following administration. At the steady state, if thedose and the frequency of administrations remain constant, theconcentration obtained will also be constant. The steady state isobtained at the end of approximately five half-lives

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. It is understood that variousbiological factors may affect the ability of a substance to perform itsintended task. Therefore, an “effective amount” or a “therapeuticallyeffective amount” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a somewhat subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein, the terms “plasma concentration,” “serum concentration,”or “concentration in the blood” of a drug or drug metabolite refers tothe serum concentration of the drug or drug metabolite.

Progesterone in serum can be analyzed by specific methods like LC-MS orwith not very specific Radioimmunoassay (RIA) e.g. Advia Centaur®System. Unless otherwise mentioned, the pharmacokinetic (PK)concentrations and related parameters in this invention are based onLC-MS analytical methods. Similarly, pregnane metabolites in serum canbe analyzed by specific methods like chromatography or the like. Thedetermination of 5-α and 5-β pregnanolone can be performed by gaschromatography-mass spectrometry with stable isotope dilution. Brieflyknown amounts of deuterium labeled analogues are added to plasma samplesthat are then equilibrated and extracted. The extracts are purified byliquid chromatography using Sephadex LH-20, derivatized and selected ionmonitoring is performed at nominal masses m/z 496 and 500, correspondingto the characteristic ions of the heptaflurobutyrates of the native andthe labeled pregnanolone, respectively.

It is to be understood that any relative comparisons of blood plasmalevels of any compound should be made with the same assay methodology,or corrections must be made to adjust for discrepancy for assayspecificity. For example, it has been reported that the results of theserum progesterone or its metabolites determined by Radio Immuno Assay(RIA) methods could be about 8 to 10 times higher than the resultsobtained by the LC-MS method.

Unless otherwise mentioned, all the serum concentrations of drug and/orits metabolite(s) disclosed in the embodiments and examples herein,refer to the “observed” concentrations, (i.e. the values represent thesum of the corresponding baseline plus additional concentration due toabsorption from the administered drug). Whereas, an “increase in theserum concentration” or “increased serum concentration” of the drugand/or its metabolite(s) refers to the corresponding base-line adjustedor base-line corrected concentration.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. As an illustration, a numerical range of “about 1 to about 5”should be interpreted to include not only the explicitly recited valuesof about 1 to about 5, but also include individual values and sub-rangeswithin the indicated range. Thus, included in this numerical range areindividual values such as 2, 3, and 4 and sub-ranges such as from 1-3,from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5,individually. This same principle applies to ranges reciting only onenumerical value as a minimum or a maximum. Furthermore, such aninterpretation should apply regardless of the breadth of the range orthe characteristics being described.

INVENTION

Natural progesterone is bioidentical to endogenous progestogenic hormoneproduced by female reproductive organs. It is highly selective toprogesterone receptors, has almost no androgenic potential, and noantiandrogenic activity. Natural progesterone also provides the benefitsof anti-mineralocorticoid activity such as reduced water and sodiumretention resulting in no weight gain. It is expected to have superiorside effect profile with respect to thrombolytic events, breast andcervical cancers, and lower risk to fetus in case of contraceptionfailure than synthetic progestins. Moreover, progesterone has littleeffect on carbohydrate metabolism compared to synthetic progestins,especially androgenic progestins. Unfortunately, natural progesterone isa weakly potent, lipophilic, and poorly water soluble steroid.Progesterone from conventional formulations and oral dosage forms, suchas immediate release oral commercial product Prometrium, result in lowand significantly variable bioavailability. Natural progesterone has abiological half-life of 3-5 hours with high blood level fluctuationindex. Further, orally-administered progesterone undergoes severalsuccessive metabolic steps in the gut, intestinal wall, and liver whichresult in the formation of pregnane metabolites that can cause variousundesirable side-effects. Therefore, it has been discovered that itwould be desirable to provide an oral dosage form that delivers naturalprogesterone in less fluctuating manner while producing reduced levelsof pregnane metabolites. Additionally, the presently disclosed oraldosage forms are formulated to provide acceptable “missed dose” safetymargins, faster contraception reversibility, and lower potential of pillrelated amenhorrea.

The disclosed oral dosage forms fill the unmet need of an effectivenatural progesterone containing oral dosage form that can be used forboth contraceptive and non-contraceptive purposes with once dailyadministration while reducing the negative metabolite side-effects andproving better “missed dose” safety margins.

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, variants, modifications, andequivalents as may be included within the spirit and scope of theinvention as defined by the appended claims.

The present invention provides for progesterone containingpharmaceutical oral dosage forms, pharmaceutical kits, and relatedmethods. In one embodiment, an oral dosage form formulated for on-goingadministration is provided. The oral dosage form includes an amount ofprogesterone and a pharmaceutically acceptable carrier. The oral dosageform can be formulated such that upon single dose administration to anon-pregnant woman in follicular phase, the oral dosage form provides aserum progesterone C_(24h) of at least 0.20 ng/mL. In one embodiment,the oral dosage form can be formulated such that upon single doseadministration to a non-pregnant woman in follicular phase, the oraldosage form can provide a serum progesterone C_(24h) of at least 0.30ng/mL, or at least 0.40 ng/mL. In one embodiment, the oral dosage formcan be formulated such that upon single dose administration to anon-pregnant woman in follicular phase, the oral dosage form can providea serum progesterone C_(24h) of about 0.20 ng/mL to about 5 ng/mL, about0.20 ng/mL to 3 ng/mL, about 0.20 ng/mL to 2 ng/mL, about 0.5 ng/mL to 3ng/mL, about 0.50 ng/mL to 2 ng/mL, or about 0.30 ng/mL to 2 ng/mL. Inanother embodiment, an oral dosage form can be formulated such that uponmultiple dose administration reaches a steady state where in serumprogesterone C_(24h) of at least 0.35 ng/mL. In another embodiment,serum progesterone C_(24h) of about 0.20 ng/mL or more upon single ormultiple dose administration can inhibit ovulation in a female subject.

In another embodiment, an oral dosage form for ongoing administration isprovided. The oral dosage form includes an amount of progesterone and apharmaceutical acceptable release modulator. The oral dosage form can beformulated such that wherein upon release rate testing of the oraldosage using a USP Type-1 dissolution apparatus in 900 mL of de-ionizedwater with 2.0% (w/v) of sodium lauryl sulfate at 100 rpm, less than 10wt % of the progesterone is released from the dosage form after about 1hour, 50 wt % or less of the progesterone is released in the first 6hours and at least 70 wt % of the progesterone is released within 12hours.

The oral dosage forms of the present invention can be formulated toprovide desirable pharmacokinetic parameters in non-pregnant femalesubjects. In one embodiment, the oral dosage forms can be formulatedsuch that upon single dose administration to a female subject the oraldosage form provides a serum total pregnane C_(max) of no greater than40 ng/mL. In one embodiment, the oral dosage form can be formulated suchthat upon single dose administration to a female subject the oral dosageform can provide a serum total pregnane C_(max) of about 5 ng/mL to 40ng/mL, about 5 ng/mL to 30 ng/mL, about 5 ng/mL to 20 ng/mL, or about 5ng/mL to 15 ng/mL. In one embodiment, the oral dosage form can beformulated such that upon single dose administration to a female subjectthe oral dosage form can provide a serum total pregnane C_(max) of 30ng/mL or less, 20 g/mL or less, or 10 ng/mL or less. In one embodiment,the oral dosage form can be formulated such that upon singleadministration to a female subject the oral dosage form can provide aserum total pregnane C_(max) of about 5 ng/mL to 40 ng/mL, about 5 ng/mLto 30 ng/mL, about 5 ng/mL to 20 ng/mL, or about 5 ng/mL to 15 ng/mL.

The oral dosage forms can be formulated such that upon single doseadministration to a non-pregnant woman in follicular phase, the oraldosage form provides a serum progesterone C_(24h) of at least 0.20 ng/mLand a serum total pregnane C_(max) of no greater than about 40 ng/mL. Inone embodiment, the oral dosage forms can be formulated such that uponsingle dose administration to a non-pregnant woman in follicular phase,the oral dosage form provides a serum progesterone C_(24h) of at least0.20 ng/mL and a serum progesterone C_(max) of no greater than about 10ng/mL. In another embodiment, the oral dosage forms can be formulatedsuch that upon single dose administration to a non-pregnant woman infollicular phase, the oral dosage form provides a serum progesteroneC_(24h) of at least 0.20 ng/mL, but less than or equal to about 1.5ng/mL. In a further embodiment, the oral dosage forms can be formulatedsuch that upon single dose administration to a non-pregnant woman infollicular phase, the oral dosage form provides a serum progesteroneC_(24h) of at least 0.20 ng/mL and a serum allopregnanolone C_(max) ofno greater than about 10 ng/mL. In still a further embodiment, the oraldosage forms can be formulated such that upon single dose administrationto a non-pregnant woman in follicular phase, the oral dosage formprovides a serum progesterone C_(24h) of at least 0.20 ng/mL when thedosage form includes progesterone in an amount of about 200 mg to about600 mg, and in a specific embodiment, 400 mg.

In another embodiment, the oral dosage forms can be formulated such thatupon single dose administration to a female subject the oral dosage formprovides a serum progesterone C_(max) of no greater than 10 ng/mL. Inanother embodiment, the oral dosage forms can be formulated such thatupon single dose administration to a female subject the oral dosage formprovides a serum progesterone C_(max) of about 8 ng/mL or less, about 7ng/mL or less, about 6 ng/mL or less, or about 5 ng/mL or less.

In still a further embodiment, the oral dosage forms can be formulatedsuch that upon single dose administration to a female subject the oraldosage form provides a serum progesterone C_(24h) of 1.5 ng/mL or less.In a further embodiment, the oral dosage forms can be formulated suchthat upon single dose administration to a female subject the oral dosageform provides a ratio of serum progesterone C_(max) to C_(24h) that isabout 1:1 and about 10:1. The oral dosage forms can also be formulatedsuch that upon single dose administration to a female subject the oraldosage form can provide a serum allopregnanolone C_(max) of no greaterthan 10 ng/mL. In one embodiment, the oral dosage forms can beformulated such that upon single dose administration to a female subjectthe oral dosage form can provide a serum allogregnalone C_(max) of about2 ng/mL to 10 ng/mL, about 2 ng/mL to 8 ng/mL, about 2 ng/mL to 6 ng/mL,or from about 1 ng/mL to 5 ng/mL. The oral dosage forms can also beformulated such that upon single dose administration to a female subjectthe oral dosage form can provide a serum allopregnanolone C_(max) of nogreater than about 8 ng/mL or less, about 7 ng/mL or less, about 6 ng/mLor less, or about 4 ng/mL or less. In one embodiment the oral dosageforms can also be formulated such that upon single dose administrationto a female subject, the oral dosage form can provide a serumallopregnanolone C_(max) of about 2 to 10 ng/mL, about 2 to 8 ng/mL;about 2 to 6 ng/mL; or about 1 to 5 ng/mL.

In a further embodiment, the oral dosage form can, upon single doseadministration to a female subject, provide a ratio of serumallopregnanolone C_(max) to serum progesterone C_(24h) of not more than50:1. In an additional embodiment, the oral dosage form can, upon singledose administration to a female subject in follicular phase, provide aratio of serum allopregnanolone C_(max) to serum progesterone C_(24h) ofabout 7.8:1 to about 1:1.

Upon single dose administration to a female subject, the oral dosageform can provide an allopregnanolone serum C_(ave(0-24)) of at leastabout 0.5 ng/mL. In another embodiment, the upon single doseadministration to a female subject, the oral dosage form can provide anallopregnanolone serum C_(ave(0-24)) of about 0.5 ng/mL to about 10ng/mL, with the allopregnanolone C_(ave(0-24)) being measured using theconventional radio immune assay method. Still further, in oneembodiment, the oral dosage form can, upon single dose administration toa female subject, provide a serum progesterone C_(36h) of not less than0.20 ng/mL. Still further, in another embodiment, the oral dosage formcan provide to a female subject, a steady state serum progesteroneC_(36h) of not less than 0.20 ng/mL.

In another embodiment, upon single dose administration to a femalesubject the oral dosage form can provide a serum progesteroneAUC_(12-24h) (ng*h/mL) to administered progesterone dose (mg) ratio ofat least 0.005 (ng*h/ml)/mg. In still a further embodiment, upon singledose administration to a female subject, the oral dosage form canprovide a ratio of administered progesterone dose (mg) to serumprogesterone C_(24h) (ng/mL) of about 100 mg/(ng/ml) to about 1000(ng/ml)/mg. In another embodiment, upon single dose administration to afemale subject, the oral dosage form can provide a ratio of administeredprogesterone dose (mg) to serum progesterone C_(36h) (ng/mL) of about100 mg/(ng/ml) to about 1000 (ng/ml)/mg. In another embodiment, uponsingle dose administration to a female subject, the oral dosage form canprovide a ratio of administered progesterone dose (mg) to serum totalpregnane C_(max) (ng/mL) of at least 20 (ng/ml)/mg. In anotherembodiment, upon single dose administration to a female subject, theoral dosage form can provide a ratio of administered progesterone dose(mg) to serum allopregnanolone C_(max) of at least 50 mg/(ng/mL).

The oral dosage forms can also provide other pharmacokinetic parameterssuch as, upon single dose administration to a female subject, the oraldosage form can provide a progesterone C_(ave(12-24)) of at least about0.11 ng/mL. In one embodiment, the oral dosage form can be such thatupon single dose administration to a subject the oral dosage formprovides a progesterone AUC₁₂₋₂₄ of at least 3 ng*h/mL. In anotherembodiment, upon single dose administration to a female subject the oraldosage form can provide an allopregnanolone C_(max) of not more thanabout 10 ng/mL. In another embodiment, upon single dose administrationto a female subject the oral dosage form can provide a progesteroneC_(24h) of at least about 0.2 ng/mL. In another embodiment, upon singledose administration to a female subject the oral dosage form can providea serum progesterone C_(36h) of not less than about 0.20 ng/mL. Inanother embodiment, upon single dose administration of theprogesterone-containing oral dosage form to a female subject, theprogesterone-containing oral dosage form can provide a ratio of serumprogesterone C_(24h) to progesterone dose administered (mg) of at leastabout 3.33×10⁻⁴ (ng/ml)/mg. In another embodiment, upon single doseadministration of the progesterone-containing oral dosage form to afemale, the progesterone-containing oral dosage form can provide a ratioof serum progesterone C_(36h) (ng/mL) to progesterone dose administered(mg) of at least about 3.33×10⁻⁴ (ng/ml)/mg. In still anotherembodiment, upon single dose administration of one of theprogesterone-containing oral dosage forms to a female, theprogesterone-containing oral dosage form can provide a an allallopregnanolone serum C_(ave (0-24)) of at least 0.3 ng/mL.

The oral dosage forms of the present disclosure can be formulated tohave progesterone release rates that are effective in achievingdesirable delivery parameters. In one embodiment, the oral dosage formcan have an in vitro release rate such that, when measured using a USPType-1 dissolution apparatus in 900 mL of de-ionized water with 2.0%(w/v) of sodium lauryl sulfate at 100 rpm, about 10 wt % or less of theprogesterone in the oral dosage form is released in the first 60 minutesand at least 70 wt % of the progesterone is released from the oraldosage form within 12 hours. In one embodiment, the oral dosage form canbe formulated such that upon in vitro dissolution using the aboveparameters the oral dosage form releases less than 25 wt % ofprogesterone in the first three hours. In another embodiment, the oraldosage form can be formulated to release substantially all of theprogesterone within the about 22 hours.

The oral dosage forms of the present disclosure can be formulated toinclude from about 100 mg to about 600 mg of progesterone. In anotherembodiment, the oral dosage form can include about 200 mg to about 600mg of progesterone. In yet a further embodiment, the oral dosage formcan include about 300 mg to about 500 mg. In yet another embodiment, theoral dosage form can include about 200 to about 400 mg. In a furtherembodiment, the oral dosage form can include 400 mg progesterone. In afurther embodiment, the oral dosage form can include 200 mgprogesterone. The progesterone can comprise from 15 wt % to about 45 wt% of the oral dosage form. In one embodiment, the progesterone cancomprises from about 15 wt % to about 45 wt % of the oral dosage form.The progesterone can be present in any form known in the art. As needed,in the compositions and forms of the present invention, the progesteronecan be micronized, nano-sized, and/or in amorphous forms. In oneembodiment, the progesterone can be present or added to the oral dosageform in an untreated form such as unmicronized, unmilled and/or unsievedforms. In another embodiment, the oral dosage form can include acombination of these forms. In another embodiment, the progesterone canbe present or added to the oral dosage form as treated form such asmicronized, nano-sized, milled or sieved forms, or combinations thereof.The progesterone can be solubilized in one or more of the othercomponents of the oral dosage form, such as the carrier, or it can besuspended within the oral dosage form. The suspended portion ofprogesterone may be partially or completely in unmicronized, milled,sieved, or amorphous forms or combinations thereof.

The progesterone in the oral dosage forms of the present invention canbe partially or fully in the form of a high-energy solid which increasesthe release rate in an aqueous medium significantly compared to at leastone of its unmilled or unmicronized crystalline forms (low energyforms). Examples of high-energy forms include amorphous forms and thelike. In one embodiment the high-energy form progesterone of presentinvention may be physico-chemically pure. In yet another embodiment thehigh-energy form progesterone can be physically and/or chemicallyassociated with at least one additional substance, such as for examplealcohol, pyrollidone, cellulose, polyol, polyethylene glycol, dextrins,cyclodextrins and the like. Several methods known in the art may be usedto produce the high-energy form progesterone of the present invention,for example co-precipitation, solid-solution, co-melting, co-grinding,spray drying with co-solvent, controlled precipitation fromsuper-saturated solutions, solidified supersaturated solutions, andcombinations thereof.

In some embodiments, the oral dosage forms of the present invention canbe formulated to include an estrogenic agent. Non-limiting examples ofestrogenic agents that can be included in the oral dosage forms includeestradiol, conjugated estradiol, conjugated equine estrogens, esterifiedestradiol, and combinations thereof. In one embodiment, the estrogenicagent can be estradiol, ethinyl estradiol, estradiol valerate, orcombinations thereof. The estrogenic agent can be a bio-identicalestrogenic agent. The estrogenic agent can present in the oral dosageform in an amount of 0.001 mg to about 7.5 mg. In another embodiment,the estrogenic agent can be ethinyl estradiol and can be present in theoral dosage form in an amount of about 0.01 mg to about 0.05 mg. In aspecific embodiment, the ethinyl estradiol can be present in the oraldosage form in an amount of about 0.01 mg to about 0.1 mg. In anotherspecific embodiment, ethinyl estradiol amount is about 0.030 mg in thedosage form. In another embodiment, the estrogenic agent can beestradiol valerate and can be present in the oral dosage form in anamount of about 0.75 mg to about 7.5 mg. In a specific embodiment, theestrogenic agent can be estradiol valerate and can be present in theoral dosage form in an amount of about 1.5 mg to about 5.5 mg. Inanother embodiment, the estrogenic agent can be estradiol and can bepresent in the oral dosage form in an amount of 0.5 mg to about 5 mg. Ina specific embodiment, the estrogenic agent can be estradiol and theestradiol can be present in the oral dosage form in an amount of 1 mg toabout 5 mg. In another specific embodiment, the estrogenic agent can beestradiol and the estradiol can be present in the oral dosage form in anamount of 1 mg to about 3.5 mg. The estrogenic agent can be present inthe oral dosage form in an amount such that the ratio (w/w) of theamount of estrogenic agent to the amount of progesterone in the oraldosage form is about 3×10⁻⁵:1 to about 3×10⁻²:1.

The oral dosage forms of the present disclosure can include one or morepharmaceutically acceptable carrier. The pharmaceutically carrier can beselected from a wide range of compounds and classes of compounds. Thepharmaceutically acceptable carrier can comprise from 55 wt % to about85 wt % of the oral dosage form. In one embodiment, the pharmaceuticallyacceptable carrier can comprise about 67 wt % to 82 wt % of the oraldosage form. In one embodiment, the pharmaceutically acceptable carriercan comprise about 50 wt % to 75 wt % of the oral dosage form.

Non-limiting examples of compounds that can be used as at least a partof the pharmaceutically acceptable carrier include without limitationcelluloses; dextrins, gums, carbomers, methacrylates, sugars, lactoses,inorganic carbonates, oxides, chlorides, sulphates and the like; saltsof calcium; salts of magnesium; salts of fatty acids; inorganic andorganic acids, bases and salts; propylene glycol; glycerols; fattyacids; fatty alcohols; fatty acid esters; glycerol esters; mono-, di- ortriglycerides; edible oils; omega oils; vegetable oils, hydrogenatedvegetable oils; partially or fully hydrogenated vegetable oils; glycerolesters of fatty acids; waxes; alcohols; gelatin; polyethylene glycol;polyethylene oxide co-polymers; silicates; antioxidants, tocopherols,sugar stearates, starches, shellac, resins, proteins, acrylates; methylcopolymers; polyvinyl alcohol; starch; phthalates; and combinationsthereof.

In one embodiment, the carrier can include at least one componentselected from celluloses, dextrins, gums, carbomers, methacrylates,inorganic carbonates, salts of calcium, salts of magnesium, fatty acids,fatty acid esters, gelatin, lactoses, polyethylene glycol, polyethyleneoxide co-polymers, silicates, partially hydrogenated vegetable oils,fully hydrogenated vegetable oils, waxes, antioxidants, tocopherol,sugar stearates, starches, shellac, resins, proteins, and combinationsthereof.

In another embodiment, the carrier can include at least one componentselected from celluloses, dextrins, gums, carbomers, methacrylates,sugars, lactoses, inorganic carbonates, salts of calcium, salts ofmagnesium, salts of fatty acids, inorganic and organic acids, bases andsalts, propylene glycol, glycerols, fatty acids, fatty alcohols, fattyacid esters, glycerol esters, mono-glycerol esters of fatty acids,di-glycerol esters of fatty acids, mixtures of mono-glycerol anddi-gylcerol esters of fatty acids, omega oils, waxes, alcohols, gelatin,polyethylene glycol, polyethylene oxide co-polymers, silicates,antioxidants, tocopherol, sugar stearates, starches, shellac, resins,proteins, acrylates, methyl copolymers, polyvinyl alcohol, starch,phthalates, and combinations thereof.

It is important to note that carrier compositions used in the presentinvention may serve multiple functional purposes within the oral dosageform. For example, a carrier may also function as a disintegrant orrelease modulator. In one aspect, the pharmaceutically acceptablecarrier can include a release modulator. The release modulator cancomprise about 8 wt % to about 80 wt % of the oral dosage form. Inanother embodiment, the release modulator can comprise about 20 wt % toabout 80 wt % of the oral dosage form. In one embodiment, the releasemodulator can comprise about 25 wt % to about 80 wt %, 30 wt % to about70 wt %, 35 wt % to about 70 wt %, 40 wt % to about 65 wt %, about 40 wt% to about 60 wt %, about 5 wt % to about 35 wt %, or about 8 wt % toabout 20 wt %, each based on entire oral dosage form.

In one embodiment, the release modulator can be present in an amountsuch that the ratio of the release modulator to the amount ofprogesterone is from about 0.75:1 to about 4:1. In another embodiment,the ratio of release modulator to the amount of progesterone can be fromabout 1.3:1 to about 3:1. In another specific embodiment, the ratio ofrelease modulator to the amount of progesterone can be from about 1:1 toabout 2:1. In another specific embodiment, the ratio of releasemodulator to the amount of progesterone can be from about 1:1, about1.5:1, about 2:1 or about 3:1.

In one embodiment, the release modulator can be selected from compoundssuch as celluloses; gums; xanthan gum; polyethylene glycol, particularlyhigh molecular weight; polyethylene oxide co-polymers;2,3-dihydroxypropyl methacrylate (DHPMA) and 2-hydroxyethyl methacrylate(HEMA); chitosan; dextrins; sugars and sugar esters; carbomers;polyvinyl pyrrolidones; starches; croscarmelloses; block copolymers,graft copolymers of lactic acid, glycolic acid, epsilon-caprolactone,lactic-co-glycolic acid oligomers, trimethylene carbonate, anhydrides,amino acids acrylates; lipophilic resins; ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl ethylcellulose (CMEC),hydroxyethyl cellulose (HEC), cellulose acetate (CA), cellulosepropionate (CPr), cellulose butyrate (CB), cellulose acetate butyrate(CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate(CAT), hydroxypropylethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), ion-exchange resin; poloxamers;and ethylhydroxy ethylcellulose (EHEC) tocopherol; shellac; fatty acids;mono-, di-, tri-esters of fatty acids with glycerol; sucrose esters withfatty acids; cetyl alcohol; stearic acid; glyceryl monosterate; glyceryldistearate; glyceryl tristearate; glyceryl palmitostearate; hydrogenatedcastor oil; butyl and glycol esters of fatty acids; oleic acid; cetylalcohol; stearyl alcohol; cetostearyl alcohol; hydrogenated vegetableoil; waxes; bees wax; lard; omega fatty acid esters; hydrogenatedsoybean oil; hydrogenated vegetable oil; hydrogenated cottonseed andcastor oil; partially hydrogenated soybean oil; partially hydrogenatedcastor oil; partially soy and cottonseed oil; phospholipids;hydrogenated oils, and their derivatives and combinations thereof. Theabove list should not be construed as being limiting to the types andnumber of compounds that can be used as release modulators.

In one embodiment, the release modulator can be selected from compoundssuch as celluloses, gums, carbomers, methacrylates, polyethylene glycol,polyethylene oxide co-polymers, acrylates, methyl copolymers, polyvinylalcohol, povidones, phthalates, fatty acids, hydrogenated vegetableoils, and mixtures thereof. Non-limiting additional examples of releasemodulators that can be included as the carrier or a component of thecarrier can include: polyethylene glycols having a weight averagemolecular weight of about 1000 and more, carbomer, methyl methacrylatecopolymers, methacrylate copolyers, hydroxypropyl methyl cellulose,hydroxypropyl cellulose, cellulose acetate phthalate, ethyl cellulose,methyl cellulose and their derivatives, ion-exchange resin, mono- di-tri-esters of fatty acids with glycerol and mixtures thereof, tocopheroland its esters, sucrose esters with fatty acids, polyvinyl pyrollidone,xanthan gums, cetyl alcohol, waxes, fats and oils, proteins, alginate,polyvinyl polymers, gelatins, organic acids, and their derivatives andcombinations thereof. In one embodiment, the release modulator can beselected from compounds such as methyl celluloses, carboxymethylcelluloses, ethyl celluloses, hydroxypropyl celluloses, hydroxypropylmethyl celluloses, croscarmelloses, carbomers, polyvinyl pyrrolidones,gums, stearic acid, glyceryl stearates, sugar stearates, gelatins,polyethylene glycols having a weight average molecular weight of about100 or more, methyl methacrylate co-polymers, cellulose acetates,cellulose acetate phthalates, and mixtures thereof.

In one embodiment, the release modulator can include a cellulose, andthe cellulose can be selected from such compounds as methyl cellulose,carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, and mixtures thereof. Other cellulosesor cellulosics that can be used include microcrystalline cellulose,ethyl cellulose (EC), carboxymethyl ethylcellulose (CMEC), hydroxyethylcellulose (HEC), cellulose acetate (CA), cellulose propionate (CPr),cellulose butyrate (CB), cellulose acetate butyrate (CAB), celluloseacetate phthalate (CAP), cellulose acetate trimellitate (CAT),hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl celluloseacetate trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). Aparticularly preferred class of such cellulosics comprises variousgrades of low viscosity (MW less than or equal to 50,000 daltons) andhigh viscosity (MW greater than 50,000 daltons) HPMC. Commerciallyavailable low viscosity HPMC polymers include the Dow METHOCEL® seriesE5, E15LV, E50LV and K100LY, while high viscosity HPMC polymers includeE4MCR, E10MCR, K4M, K15M and K100M; especially preferred in this groupare the METHOCEL® K series. Other commercially available types of HPMCinclude the Shin Etsu METOLOSE® 90SH series.

In one embodiment, when the release modulator is a cellulose, the ratio(w/w) of the amount release modulator to the amount of the progesteronein the oral dosage form can be from about 0.75:1 to about 4:1. Inanother embodiment, when the release modulator can be a cellulose, andthe ratio (w/w) of the amount release modulator to the amount of theprogesterone in the oral dosage form can be from about 1.3:1 to about2.7:1. In another specific embodiment, the ratio (w/w) can be from about1:1. In yet a further specific embodiment, the ratio of releasemodulator to the amount of progesterone (w/w) can be about 1.5:1, about1.8:1, about 2:1, or about 2.25:1.

In one embodiment, the release modulator can be a hydrophilic releasemodulator. When present, the hydrophilic release modulator can compriseall or a portion of the release modulator. In one embodiment, thehydrophilic release modulator can be present in an amount of about 10 wt% to about 65 wt % of the dosage form. Non-limiting examples ofhydrophilic release modulators include celluloses; gums; xanthan gum;polyethylene glycol, particularly high molecular weight; polyethyleneoxide co-polymers; 2,3-dihydroxypropyl methacrylate (DHPMA) and2-hydroxyethyl methacrylate (HEMA); chitosan; dextrins; sugars and sugaresters; carbomers; polyvinyl pyrrolidones; starches; croscarmelloses;block copolymers, graft copolymers of lactic acid, glycolic acid,epsilon-caprolactone, lactic-co-glycolic acid oligomers, trimethylenecarbonate, anhydrides, and amino acids acrylates. Non-limiting examplesof hydrophilic celluloses or hydrophilic cellulosics that can usedinclude carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl celluloseacetate succinate (HPMCAS). A particularly preferred class of suchcellulosics comprises various grades of low viscosity (MW less than orequal to 50,000 daltons) and high viscosity (MW greater than 50,000daltons) HPMC. Commercially available low viscosity HPMC polymersinclude the Dow METHOCEL® series E5, E15LV, E50LV and K100LY, while highviscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M;especially preferred in this group are the METHOCEL® K series. Othercommercially available types of HPMC include the Shin Etsu METOLOSE®90SH series.

Lipophilic release modulators may also be used. The lipophilic releasemodulator can be either a non-lipid lipophilic release modulator or alipidic lipophilic release modulator. When present, the amount oflipophilic release modulator can vary depending on various factors. Inone embodiment, the lipophilic release modulator can comprise about 8 wt% to about 50 wt % of the oral dosage form. In another embodiment, thelipophilic release modulator can comprise about 5 wt % to about 30 wt %,8 wt % to 20 wt %, or 20 wt % to about 50 wt %, each based on the totaloral dosage form. In another embodiment, the lipophilic releasemodulator can be a non-lipidic lipophilic release modulator and can bepresent at about 8 wt % to about 35 wt % of the oral dosage form. Inanother embodiment, the lipophilic release modulator can be a lipidicrelease modulator and can be present at about 10 wt % to about 50 wt %of the oral dosage form.

Non-limiting examples of non-lipidic lipophilic release modulators thatcan be used include lipophilic resins; ethyl cellulose (EC), methylethylcellulose (MEC), carboxymethyl ethylcellulose (CMEC), hydroxyethylcellulose (HEC), cellulose acetate (CA), cellulose propionate (CPr),cellulose butyrate (CB), cellulose acetate butyrate (CAB), celluloseacetate phthalate (CAP), cellulose acetate trimellitate (CAT),hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl celluloseacetate trimellitate (HPMCAT), ion-exchange resin; poloxamers; andethylhydroxy ethylcellulose (EHEC) tocopherol; shellac; and combinationsthereof. Non-limiting examples of lipidic lipophilic release modulatorsinclude fatty acids; mono-, di-, tri-esters of fatty acids withglycerol; sucrose esters with fatty acids; cetyl alcohol; stearic acid;glyceryl monosterate; glyceryl distearate; glyceryl tristearate;glyceryl palmitostearate; hydrogenated castor oil; butyl and glycolesters of fatty acids; oleic acid; cetyl alcohol; stearyl alcohol;cetostearyl alcohol; hydrogenated vegetable oil; waxes; bees wax; lard;omega fatty acid esters; hydrogenated soybean oil; hydrogenatedvegetable oil; hydrogenated cottonseed and castor oil; partiallyhydrogenated soybean oil; partially hydrogenated castor oil; partiallysoy and cottonseed oil; phospholipids; hydrogenated oils, and theirderivatives and combinations thereof.

In one embodiment, the pharmaceutically acceptable carrier canoptionally include at least one surfactant. When present, the surfactantcan comprise about 0.1 wt % to about 25 wt % of the oral dosage form. Inone embodiment, the surfactant can comprise about 4 wt % to about 10 wt% of the oral dosage form. In one embodiment, the surfactant can be ahydrophilic surfactant. A hydrophilic surfactant has a surface activeproperty and that has an HLB value of 10 or more. In one embodiment, thehydrophilic surfactant can be selected and present in an amount suchthat the hydrophilic surfactant solubilizes less than 10 wt % of theprogesterone in the oral dosage form. The hydrophilic surfactants can bean anionic or non-ionic surfactant. Non-limiting examples of hydrophilicsurfactants that can be included in the oral dosage forms include sodiumlauryl sulphate, polysorbate 80, sodium docusate, polyoxyl castor oils,polyoxyl hydrogenated castor oils etc., and mixtures thereof. In anotherembodiment, the hydrophilic surfactant can be present in an amount suchthat the ratio (w/w) of the total amount of the hydrophilic surfactantto the amount of progesterone in the dosage form is about 1:10 to about1:2. In another embodiment, the ratio (w/w) of the total amount of thehydrophilic surfactant to the amount of progesterone in the dosage formcan be from about 1:9 to about 1:2, about 1:8 to about 1:2, about 1:7 toabout 1:4, or about 1:6 to about 1:4. In another embodiment, thehydrophilic surfactant can be present in an amount such that the ratio(w/w) of the total amount of the hydrophilic surfactant to the amount oftotal release modulator in the dosage form is from about 1:5 to about1:15 or about 1:5 to about 1:10. In a particular embodiment, theprogesterone containing oral dosage form can include progesterone, arelease modulator agent, and optionally a hydrophilic surfactant. Theprogesterone can be present in an amount from about 10 wt % to 40 wt %of the dosage form and the total hydrophilic surfactant, when present,can comprise about 4 wt % to 10 wt % of the oral dosage form. The oraldosage form can be formulated to have a ratio (w/w) of release modulatorto the amount of progesterone in the dosage form of about 1:1 to 3:1.

In another embodiment, progesterone containing oral dosage forms caninclude progesterone, a release modulator agent, and optionally ahydrophilic surfactant. The progesterone can be present in an amount ofabout 20 wt % to 40 wt % of the dosage form. The ratio of the amount ofthe release modulator to the amount of the progesterone amount in thedosage form can be about 1.3:1 to 2.3:1 and the optional surfactant doesnot exceed 10 wt % of the dosage form. In another embodiment, theprogesterone-containing oral dosage form can include progesterone, arelease modulator agent and a hydrophilic surfactant. The progesteronecan be present in an amount of about 20 wt % to 40 wt % of the oraldosage form. The total hydrophilic surfactant can be present in anamount of about 4 wt % to 8 wt % of the oral dosage form and the ratio(w/w) of the amount of the release modulator to the amount ofprogesterone in the oral dosage form can be about 1.3:1 to 2.3:1.

In one embodiment, the oral dosage form can be substantially free ofedible oils. In another embodiment, the oral dosage form can besubstantially free of oils having a carbon chain length of 12 to 18carbons. In another embodiment, the oral dosage form can besubstantially free of hydrophilic surfactants. The oral dosage form canalso include one or more pharmaceutical aids and excipients to improveperformance, handling, or processing. Non-limiting examples includeantioxidants, binders, buffers, diluent, disintegrant, adsorbents,fillers, flavors, lactoses, inorganic carbonates, oxides, chlorides andsulphates, salts of sodium, calcium and magnesium, dextrins, salts offatty acids, inorganic and organic acids and bases, propylene glycol,glycerols, fatty acids, fatty acid esters, glycerol esters,monoglyceride, diglycerides, or triglycerides, edible oils, omega oils,vegetable oils, fatty alcohols, waxes, alcohols, gelatin, silicates,tocopherols, sugars, sugar stearates, starches, shellac, resins,proteins, polyvinyl alcohol, and combinations thereof. The oral dosageform can further include release-rate enhancers such as, for example,wetting agents, surfactants, pH modifiers, matrix materials, complexingagents, solubilizers, pigments, lubricants, glidants, and the like. Inone embodiment the compositions comprise at least one wetting agentand/or surfactant selected from the group comprising hydrophilic,lipophilic, amphiphilic, ionic, nonionic surfactants. In anotherembodiment, the composition can be substantially free of addedhydrophilic surfactants.

In one embodiment of the present invention, the oral dosage form canoptionally include edible oils in an amount not exceeding about 10 wt %of the dosage form. In a specific embodiment, the amount of edible oildoes not exceed 5 wt % of the dosage form.

In one embodiment of the present invention, the oral dosage form canoptionally include oils containing omega fatty acids. Non-limitingexamples of oils containing omega fatty acids, can include, but are notlimited to, linoleic acid (ALA), eicosapentaenoic acid (EPA), anddocosahexaenoic acid (DHA), all of which are polyunsaturated with carbonchain length greater than 20. In another embodiment omega-3 fatty acidscan be administered with progesterone concomitantly or sequentially. Theoral dosage forms of the present invention can include apharmaceutically acceptable carrier. The carrier can be a singleingredient, or a mixture of ingredients. Additionally, the carrier cantake the form of an encapsulation coat, an absorbing agent, a coatingsubstance, a controlled release device, a release modifying or releasecontrolling agent, surfactants, or a combination thereof. In oneembodiment, the carrier can be admixed with the progesterone. In anotherembodiment, the carrier can adsorb, entrap, or encapsulate at least aportion of the progesterone. In yet another embodiment, the carrier canact to solubilize the progesterone.

Non-limiting examples of fillers, or diluents include celluloses such asthose other than used to modify drug release rates from the compositionand/or dosage forms, lactose, mannitol, xylitol, dibasic calciumphosphate (anhydrous and dihydrate) and starch. Non-limiting examples ofdisintegrants include sodium starch glycolate, sodium alginate, carboxymethyl cellulose sodium, and croscarmellose sodium, and crosslinkedforms of polyvinyl pyrrolidone such as those sold under the trade nameCrospovidone (available from BASF Corporation). Non-limiting examples ofbinders can include methyl cellulose, microcrystalline cellulose,starch, and gums such as guar gum, and tragacanth. Non-limiting examplesof lubricants can include magnesium stearate, calcium stearate, andstearic acid. Non-limiting examples of preservatives can includesulfites (an antioxidant), benzalkonium chloride, methyl paraben, propylparaben, benzyl alcohol and sodium benzoate.

In another embodiment, the oral dosage form of this invention canoptionally include polyethylene glycol (PEG) having a molecular weightof about 400 to about 20,000, or mixtures of such polyethylene glycols.When included in an oral dosage form, the amount of PEG can make up lessthan 30 wt % of the oral dosage form. In one embodiment, the amount ofPEG can be about 5 wt % to about 30 wt %, about 5 wt % to about 25 wt %,about 5 wt % to about 20 wt %, about 5 wt % to about 15 wt %, or about 5wt % to about 10 wt %. In a specific embodiment, the amount of PEG canmake up about 10 wt % or less or about 5 wt % or less, of the oraldosage form.

Non-limiting examples of suspending agents or thickeners can includexanthan gum, starch, guar gum, sodium alginate, carboxymethyl cellulose,sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid, silica gel, aluminum silicate, magnesiumsilicate, and titanium dioxide. Non-limiting examples of anti-cakingagents or fillers include silicon oxide and lactose. Non-limitingexamples of solubilizers can include ethanol, propylene glycol orpolyethylene glycol.

The addition of pH modifiers such as acids, bases, or buffers may bebeneficial, retarding the release of progesterone (e.g., bases such assodium acetate or amines) or, alternatively, enhancing the rate ofrelease of progesterone (e.g., acids such as citric acid or succinicacid). Other conventional excipients may also be employed in the oraldosage forms of this invention, including those well-known in the art.Generally, excipients such as pigments, lubricants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions.

The dosage form(s) are not limited with respect to size, shape orgeneral configuration, and may be formulated into a variety of dosageforms including, but not limited to two piece hard gelatin capsules,soft gelatin capsules, beads, beadlets, granules, spherules, pellets,microcapsules, microspheres, nanospheres, nanocapsules, tablets, orcombinations thereof. Other oral dosage forms known to those of ordinaryskill in the art may also be used. In one aspect, the oral dosage formmay be a capsule or tablet. In one embodiment, the oral dosage form canbe a matrix tablet.

The progesterone of the oral dosage forms of the present invention maybe incorporated into an osmotic sustained or controlled or delayedrelease dosage form. Such dosage forms have at least two components: (a)the core which contains an osmotic agent and progesterone; and (b) awater permeable, non-dissolving and non-eroding coating surrounding thecore, the coating controlling the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusion ofsome or all of the core to the environment of use. The osmotic agentcontained in the core of this dosage form may be an aqueous-swellablehydrophilic polymer or it may be an osmogen, also known as an osmagent.The coating can be polymeric, aqueous-permeable, and can have at leastone delivery port that is pre-formed or formed in situ. Examples of suchdosage forms are well known in the art. See, for example, Remington: TheScience and Practice of Pharmacy, 20.sup.th Edition, 2000.

The oral dosage forms of the present invention can include a coating. Inone embodiment, the coating can include all or a portion of the releasemodulator. One class of preferred coating materials are thepharmaceutically acceptable methacrylic acid copolymers, which areanionic in character, based on methacrylic acid and methyl methacrylate,for example having a ratio of free carboxyl groups:methyl esterifiedcarboxyl groups of 1:<3, e.g. around 1:1 or 1:2, and with a meanmolecular weight of 135000. Some of these polymers are known and sold asenteric polymers, for example having a solubility in aqueous media at pH5.5 and above, such as the commercially available EUDRAGIT entericpolymers, such as Eudragit L 30, a cationic polymer synthesized fromdimethylaminoethyl methacrylate, Eudragit S and Eudragit NE. The coatingmay include conventional plasticizers, including dibutyl phthalate,dibutyl sebacate, diethyl phthalate, dimethyl phthalate, triethylcitrate, benzyl benzoate, butyl and glycol esters of fatty acids,mineral oil, oleic acid, stearic acid, cetyl alcohol, stearyl alcohol,castor oil, corn oil, coconut oil, and camphor oil, and other excipientssuch as anti-tack agents, glidants, etc. For plasticizers, triethylcitrate, coconut oil and dibutyl sebacate are also useful. Typically thecoating may include from about 0.1 to about 25 wt % plasticizer and fromabout 0.1 wt % to about 10 wt % anti-tack agents. The enteric coatingmay also include insoluble materials, such as shellac, alkyl cellulosederivatives such as ethyl cellulose, crosslinked polymers such asstyrene-divinylbenzene copolymer, polysaccharides having hydroxyl groupssuch as dextran, cellulose derivatives which are treated withbifunctional crosslinking agents such as epichlorohydrin,dichlorohydrin, 1,2-, 3,4-diepoxybutane, etc. The enteric coating mayalso include starch and/or dextrin. The coating, including entericcoatings, may be applied to the oral dosage form by dissolving orsuspending the enteric coating materials in a suitable solvent. Examplesof solvents suitable for use in applying a coating include alcohols,such as methanol, ethanol, isomers of propanol and isomers of butanol,ketones, such as acetone, methylethyl ketone and methyl isobutyl ketone,hydrocarbons, such as pentane, hexane, heptane, cyclohexane,methylcyclohexane, and octane; ethers, such as methyl tert-butyl ether,ethyl ether and ethylene glycol monoethyl ether; chlorocarbons, such aschloroform, methylene dichloride and ethylene dichloride;tetrahydrofuran; dimethylsulfoxide; N-methylpyrrolidinone; acetonitrile;water; and mixtures thereof.

Coating may be conducted by conventional techniques, such as by pancoaters, rotary granulators and fluidized bed coaters such as top-spray,tangential-spray or bottom-spray (Wurster coating), most preferably thelatter. One preferred coating solution consists of about 40 wt %Eudragit L30-D55 and 2.5 wt % triethylcitrate in about 57.5 wt % water.This enteric coating solution may be coated onto the core of the oraldosage form using a pan coater. The enteric coating materials listedabove can be used to granulate a progesterone containing mixture. Theresultant granulate may be filled into capsules or compressed to formtablets or caplets. The release of progesterone from the oral dosageforms or components of the dosage form (e.g. granules), of the presentdisclosure can be controlled or delayed. The oral dosage forms of thepresent invention can be formulated for once-a-day or twice daily (i.e.once every 12 hours) administration of progesterone.

The oral dosage form disclosed herein can be formulated foradministration once every 24 hours. In particular, the oral dosage formscan be formulated for administration once every 24 hours as part of adosing regimen that provides contraception. In one embodiment, the oraldosage forms can be formulated for administration once every 12 hours.The oral dosage forms can be formulated to provide contraception to anon-pregnant woman. In another embodiment, the oral dosage forms can beformulated for administration to a woman for a non-contraceptiveindication. Non-limiting examples of non-contraceptive uses for whichthe oral dosage forms may be utilized include treatment of conditionssuch as endometriosis, irregular menstrual cycles, acne, dysmenorrheaand premenstrual symptoms, dysphoric disorder, polycystic ovariansyndrome (PCOS), perimenopause, hirsutism, and combinations thereof. Inone aspect of the invention the oral dosage form can be formulated toprovide contraception to a non-pregnant female subject when administereddaily from day-1 to at least day-21 of a 28 day menstrual cycle in anormal cyclic woman.

Unless otherwise specified, the oral dosage forms of the presentinvention can be administered to a subject with a meal or a snack. Thedosage form can be administered within about 30 minutes of the start ofthe meal/snack. The administration is generally expected to be at thesame time, or about the same time every day. In one embodiment, the mealor snack can provide about 200 calories to about 1000 calories. Inanother embodiment, the oral dosage form can be administered with astandard meal. In another embodiment, the oral dosage form can beadministered with a meal that provides about 20%-50% of the caloriesfrom fat. In another embodiment, the oral dosage form can beadministered with a high-fat, high calorie meal/snack. In anotherembodiment, the oral dosage form can be administered with a meal/snackthat provides about 500 calories to about 1000 calories. In anotherembodiment, the oral dosage form can be administered with a meal thatprovides about 400 calories to about 700 calories which are derived fromfat. The compositional make-up of the meals/snack administered can varydepending on the tastes and dietary needs of the subject. In somesituations it may be beneficial to administer the oral dosage forms witha meal/snack that provides amounts of fat of 0 grams up to about 50grams. In one embodiment, the meal/snack can provide about 10 g to about50 g of fat. In yet a further embodiment, the meal can provide about 20g to about 30 g of fat. It should be noted that dosage forms of thecurrent invention can be administered to a subject under fastingcondition. Accordingly, the daily dosage regimen can be adjusted toprovide the serum progesterone C_(24h) concentration of about 0.20 ng/dLor higher.

The present invention also provides for kits used in disbursement andadministration of the oral dosage forms of the present invention. Thekit can include a plurality of doses of a progesterone-containing oraldosage form and optionally a placebo dose of an oral dosage form. Thekit can also include a set of instructions regarding use of the oraldosage forms as part of a regimen or other treatment event.

The plurality of progesterone-containing oral dosage forms can includeoral dosage forms having different doses of progesterone. For examplethe kit can include a portion of the plurality of oral dosage forms thathave 200 mg progesterone and another portion of the plurality of oraldosage forms that have 400 mg of progesterone. In other embodiments, theplurality of oral dosage forms can have the same dose of progesterone.The kit can be such that upon single dose administration of one of theprogesterone-containing oral dosage forms to a woman, theprogesterone-containing oral dosage form provides a ratio of serumprogesterone AUC₁₂₋₂₄ (ng*h/mL) to administered dose (mg) of at leastabout 1×10⁻⁰⁷ and does not exceed about 8×10⁻⁰⁷ (ng*h/ml)/mg. The kitmay further include one or more other components, including, but notlimited to 1) instructions to enable those ordinarily skilled in the artto prepare a dosage form for immediate dispensing to the subject in needof; 2) one or more containers filled with one or more of the ingredientsof the oral pharmaceutical dosage forms of the invention. Suitablecontainers include, for example, a bottle, a box, a blister card, a foilpacket, or a combination thereof; 3) a tamper proof container orpackaging; 4) other pharmaceutical dosage forms including other activeagents; 5) Notice or printed instructions: in a form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of the manufacture, use, or sale for human administrationto treat a condition that could be treated by oral progesterone therapy;6) A “planner” for monitoring and tracking administration of the oraldosage forms; 7) Containers for storing and transporting the componentsof the kit; 8) Pregnancy test kits; 9) progesterone testing materials;10) vitamins and/or nutritional supplements such as folates, omega fattyacids; 11) Anti-bacterial infection materials.

The pharmaceutical kits prepared using the oral dosage forms disclosedherein can be formulated to provide contraception to a woman or to beused for non-contraceptive treatment of a woman. In one embodiment, thekit can be formulated to provide contraception to a woman and thereversal of contraception in the woman can occur within about 4 daysfollowing cessation of use of the kit. In another embodiment, the kitcan provide a lag time to withdrawal bleeding in a woman of no more thanabout 48 hours from the time of cessation of administration of theprogesterone-containing dosage form. In one embodiment, the kit can beformulated for administration of an oral dosage once-a-day for a periodof at least 28 days. In another embodiment, the kit can be formulatedfor administration of an oral dosage once-a-day for a period of at least56 days. In another embodiment, the kit can be formulated foradministration of an oral dose once-a-day for a period of at least 84days. In some embodiments, the kit can include 1 to 7 placebo dosageforms. As set forth above in the definitions, a placebo dosage form is adosage form that contains no progesterone. The kits of the presentinvention can include any of the progesterone-containing oral dosageforms disclosed herein. In one embodiment, the kit containsprogesterone-containing oral dosage forms that are formulated to providea monophasic, biphasic or triphasic progesterone dosing regimen. Amonophasic progesterone dosing regimen is a dosing regimen in which asame dose of progesterone is administered everyday over a consecutiveday administration period of 28 days, 56 days or 84 days. Accordingly,in one embodiment, when the kit is formulated to provide a monophasicregimen, the kit includes oral dosage forms that have identical doses ofprogesterone.

A biphasic progesterone dosing regimen includes an initial progesteronedose that is administered every day during an “initial phase” or “firstphase” of the regimen that can last for a predetermined period of days.The regimen then includes a “second phase” in which a different dose ofprogesterone (usually, lower than the initial phase daily dosage amount)is administered for a predetermined period days. By way of example, aprogesterone dose of 400 mg can be administered daily in the initial orfirst phase (can be day-1 to day-14) and a progesterone dose of 200 mgis administered daily in the “second phase” (day-15 to day 28). When aplacebo (non-progesterone containing) dosage form is included in the kitfor use from day 22 to day 28, then the second phase progesterone dosingmay extend from day-15 to about day 21. This regimen is still “biphasic”in terms of progesterone dosing regimen. A “triphasic regimen” includesthree different progesterone doses in each of three phases within a28-day cycle. It can also be possible that the triphasic regimenincludes two identical progesterone dosing phases separated by adifferent progesterone dosing phase. It should be noted that anadditional active agent, such as for example estradiol, may optionallybe included along with the progesterone-containing dosage forms formonophasic, biphasic and/or triphasic progesterone dosing regimen.

The progesterone-containing dosage forms disclosed herein can providereduced dizziness associated with the oral administration ofprogesterone. A method of administering any of the oral dosage formsclaimed herein to a subject is also contemplated. The reduction indizziness associated with the administration can be quantified ormeasured by an increase in saccadic eye velocity (SEV) of the subject,as compared to the saccadic eye velocity of the subject whenadministered an equivalent dose of progesterone in dosage form that doesnot conform to the compositional requirements of the oral dosage formsdisclosed herein.

The reduction in dizziness associated with the administration can bemeasured by any known method in the art including the measurement ofsaccadic eye velocity (SEV) of the subject. Saccadic Eye Velocity (SEV)is one method of measuring extent of dizziness. When progesterone isadministered to a human subject orally, pregnane metabolite levels risedue to metabolism and lead to dizziness. A decrease in SEV can indicatethat the subject is dizzy or sedated. When a subject is dizzy thesaccadic eye velocity tends to be slower. Without wishing to be bound tothe theory, the current inventive oral dosage forms can slowly releasethe progesterone at an rate such that a rapid increase in the serumconcentration of pregnane metabolites is prevented. It is also withinthe scope of this invention that oral dosage form can provide a releaserate such that the serum pregnane metabolites (e.g. allopregnanolone)level is maintained at low levels (typically, about 8 ng/mL or less forallopregnanolone) which levels can reduce anxiety and/or facilitate“positive mood”.

In another embodiment, the progesterone-containing oral dosage formsand/or methods (regimen) of administration disclosed herein can provideseveral benefits to the user, particularly non-pregnant female usersfrom adolescent age up to menopause. In addition to the highlyeffective, safe and easily reversible contraception, the said oraldosage forms and related methods (regimen) can provide one or more ofthe following significant benefits/improvements (≧20% difference)compared to the typical progestin (non-bioidenticalprogesterone)-containing contraceptive dosage forms: 1) better cyclecontrol; 2) decreased risk of iron-deficiency anemia; 3) reduction inpremenstrual syndrome; 4) reduced cyclic depression; reduction in therisks of functional ovarian cysts, benign breast cysts, fibroadenoma andectopic pregnancy; 5) lower thrombolytic and vascular events risk; 6)reduced or no risk of loss of libido; 7) reduced or no negative effectson the carbohydrate and lipid metabolisms; 8) lower risk of adversemetabolic syndromes; 9) lower incidences of pill amenorrhea (Latent Fearof Pregnancy); 10) reduction in occurrences of mood swings/changes; 11)reduction in headache/migraine, acne formation, incidences of high bloodpressure, metrorrhagia and irregular bleeding, nausea/vomiting; 12reduction in breast pain, discomfort and/or tenderness; and 13) lowerrisk of breast cancer.

In a further embodiment, the significant advantages/improvements (with≧20% difference) of the progesterone-containing oral dosage forms andrelated methods (regimen) of administration disclosed herein compared tothe synthetic contraceptive pills include: 1) higher and specificselectivity to progesterone receptors; 2) least or no adverse-effectsdue to androgenicity (such as acne hirsutism etc.); 3) minimum impact onlipid profile; 4) reduced or no anti-androgenic andanti-mineralocorticoid activities resulting in lower risk of venousthrombosis and/or loss of libido, lower risk of body weight gain; 5)optimal half-life of the progesterone enabling reduced time (days) tofertility (reversibility of contraception) and also reduced or no riskto the fetus if pregnancy occurs; 6) reduced occurrences of pillamenorrhea.

In another embodiment, the progesterone-containing oral dosage formsand/or methods (regimen) of administration disclosed herein providessignificant advantages/improvements (≧20% difference) to nursing motherswishing to adopt supplemental contraception, in terms of least or noadverse effect on the child being nursed, compared. In anotherembodiment, the progesterone-containing oral dosage forms and/or methods(regimen) of administration disclosed herein which include estradiol, asignificant improvement in menstrual cycle control can be achieved ascompared to the typical combination contraceptive pills containingnon-bioidentical progestogen and estrogen agents.

In a specific embodiment, the progesterone-containing oral dosage formsand related methods (regimen) of administration for contraceptiondisclosed herein can provide significant advantages/improvements (≧20%difference) compared to an equivalent progesterone dose administered inthe form of conventional progesterone-containing dosage forms (for e.g.capsule comprising micronized progesterone suspended in edible oil)including: 1) larger safety time window for a missed dose; 2)predictability in withdrawal bleeding; 3) reversibility to fertility; 4)lower fluctuation in the serum concentrations of progesterone andpregnane metabolites between consecutive dose administration.

EXAMPLES

The following examples are provided to promote a more clearunderstanding of certain embodiments of the present invention, and arein no way meant as a limitation thereon. The compositions may besuitably modified by a person skilled in the art to get dosage formssuch as capsule, tablet, mould, beads, granules and the like. Note that,the progesterone in example oral dosage forms listed below can be eithertreated (milled, micronized, or nanosized) or untreated, as indicated,where not specified can be either.

Example 1 Progesterone Containing Oral Dosage Forms for Oral Delivery

Several progesterone-containing dosage forms are prepared using thecomponents as set forth in Tables I-IV. The dosage forms are providedfor ease of understanding the invention and are generally solid dosageforms such as a tablet. The dosage forms are prepared by mixing therelease modulator, processing aids and the optional surfactant withprogesterone to form a homogenous powder blend. The powder blend can becompressed to form tablets by direct compression or after dry or wetgranulation process steps. In case of wet granulation, a solution ofbinder (such as PVP K30) can be used for granulation. The bindersolution may optionally contain a portion (or all) of the amount of thesurfactant, when a surfactant is present in the dosage form. Followinggranulation, the resultant product can be dried and compressed intotablets.

For instance, if desired, dosage forms can be prepared by wetgranulation process using a binder solution of a 6-12% w/w Povidone K30(a processing aid) in DI water. When a surfactant is present it can bepresent in the dry components or in the wet binder solution. Forexample, when a surfactant is present about 25-50% of the amount of thesurfactant can be dissolved in the DI water. The release modifying (orrelease modulating) agent (if present), the remaining amount of thesurfactant and filler/diluent (microcrystalline cellulose; processingaid) are homogenously blended with the progesterone in the shallow bowlof a conventional wet granulator (Diosna, Collette or equivalent) andgranulated with the binder solution. The wet granulate is dried (e.g. ina tray dryer) to a moisture content of less than about 2% w/w. The driedgranules are sized using a QaudroComill (or equivalent), mixed withprocess aids such as silicon dioxide and purified talc in a double coneblender, lubricated with magnesium stearate and/or stearic acid andfinally compressed to get tablet dosage forms having required hardness(e.g. about 10-18 kP).

TABLE IA DOSAGE FORMS DOSAGE FORM # 1 2 3 4 5 6 7 8 9 10 11 Component %w/w Progesterone (treated) 15-40 15-40 — 15-45 18-40 18-33 18-33 24 5024 12 Progesterone (untreated) — — 15-40 — — — — — — — — HydrophilicRelease 0 18  0-60 25-80 35-70 45-65 45-60 53 — 18 82 Modulator (e.g.HPMC, HPC, CMC, methacrylates, PLGA) Surfactant (e.g. polysorbate 0 2525  0-25  0-25  0-20  5-10  6 0-25 0-25 5-10 80, polyoxyl 40hydrogenated castor oil, Sodium Lauryl sulfate, Sodium docusate)Processing Aids (e.g. filler, q.s. to q.s. to q.s. to q.s. to q.s. toq.s. to q.s. to q.s. to q.s. to q.s. to q.s. to binder, lubricant etc.)100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%

TABLE 1B DOSAGE FORMS WITH PHARMACOKINETIC RESULTS DOSAGE FORM # 1 2 3 45 6 SERUM PROGESTERONE (P) PK PARAMETERS, AFTER SINGLE DOSE(CONCENTRATIONS PER UNIT MEASURE INDICATED) P-C₂₄, [ng/mL] <0.2 <0.2<0.2 >0.2 >0.2 >0.2 P-C₃₆, [ng/mL] <0.20 <0.20 <0.20 ≧0.20 ≧0.20 ≧0.20P-C_(max), [ng/mL] ≧10 ≧10 ≧10 ≦10 ≦10 ≦10 P-C_(max) to C₂₄ >10 >10 >101-10 1-10 1-10 P-AUC₁₂₋₂₄, [ng * h/mL] <2.5 <2.5 <2.5 3-6  3-6  3-6 P-AUC 12-24/P-dose, <0.004 <0.004 <0.004 0.005-0.03  0.005-0.03 0.005-0.03  [(ng * h/mL)/mg] P-dose/C₂₄, [mg/(ng/mL)] >1000 >1000 >1000100-1000 100-1000 100-1000 TOTAL PREGNANE (PG) METABOLITES(CONCENTRATIONS PER UNIT MEASURE INDICATED) PG-C_(max),[ng/mL] >10 >10 >10 <10 <10 <10 P-dose/PG-C_(max) [mg/(ng/mL)] <10 <20<20 20-180 20-180 20-180 PG-C_(ave(0-24)) [ng/mL] >2.5 >2.5 >2.50.5-2.0  0.5-2.0  0.5-2.0  TOTAL ALLOPREGNANOLONE (AP) (CONCENTRATIONSPER UNIT MEASURE INDICATED) AP-C_(max), [ng/mL] >10 >10 >10 0.2-5.0 0.2-5.0  0.2-5.0  AP-C_(ave(0-24)), [ng/mL] 1.5-4.0 1.5-4.0 1.5-4.00.3-1.45 0.3-1.45 0.3-1.45 AP-C_(max) to P-C₂₄ >75 >75 >75 2-20 2-202-20 P-dose/AP-C_(max) <20 <20 <20 50-300 50-300 50-300 [mg/(ng/mL)]DOSAGE FORM # 7 8 9 10 11 SERUM PROGESTERONE (P) PK PARAMETERS, AFTERSINGLE DOSE (CONCENTRATIONS PER UNIT MEASURE INDICATED) P-C₂₄,[ng/mL] >0.2 0.32 <0.2 <0.2 <0.2 P-C₃₆, [ng/mL] ≧0.20 ≧0.20 <0.20 <0.20<0.20 P-C_(max), [ng/mL] ≦10 ≦10 ≦10 ≧10 ≦10 P-C_(max) to C₂₄ 1-101.44 >10 >10 1-3 P-AUC₁₂₋₂₄, [ng * h/mL] 3-6  4.5 <2.5 <2.5 0.5-2  P-AUC 12-24/P-dose, 0.005-0.03  0.0225 <0.004 <0.004 <0.004 [(ng *h/mL)/mg] P-dose/C₂₄, [mg/(ng/mL)] 100-1000 628 >1000 >1000 1500-2500TOTAL PREGNANE (PG) METABOLITES (CONCENTRATIONS PER UNIT MEASUREINDICATED) PG-C_(max), [ng/mL] <10 3.03 >20 >10 1.0 P-dose/PG-C_(max)[mg/(ng/mL)] 20-180 66 <20 <20 200 PG-C_(ave(0-24)) [ng/mL] 0.5-2.0 1.75 >2.5 >2.5 <0.5 TOTAL ALLOPREGNANOLONE (AP) (CONCENTRATIONS PER UNITMEASURE INDICATED) AP-C_(max), [ng/mL] 0.2-5.0  1.6 >10 >10 <0.2AP-C_(ave(0-24)), [ng/mL] 0.3-1.45 0.85 1.5-4.0 1.5-4.0 <0.3 AP-C_(max)to P-C₂₄ 2-20 6.12 >150 >100 >20 P-dose/AP-C_(max) 50-300 126 11 20 >300[mg/(ng/mL)]

Dosage forms 4-8 have levels of compositional components (progesterone,hydrophilic release modulator and surfactant, if present) that providedesired performance consistent with embodiments of the invention. Thesedosage forms contain progesterone in the range of 100-600 mg and canalso contain an estrogen (0.010 to 0.1 mg of ethinyl estradiol, 0.05 to5 mg of estradiol or estradiol valerate). Further, these dosage forms,when prepared without progesterone can function as placebo (with orwithout Estrogen). For multi-phasic applications, the dose ofprogesterone and/or estrogen can be varied in the dosage form as acomponent of a kit.

TABLE-IIA DOSAGE FORMS DOSAGE FORM # 12 13 14 15 16 17 18 19 20 21 22COMPONENT (% W/W) Progesterone 15-40  15-40 18-33 15-40 15-40 18-33 2525 25 25  8 Non-lipidic Lipophilic 8-35 10-20 10-20  5-30  8-20  8-20 5 5 55 5 40 Release modulator (e.g. Ethyl cellulose cellulose acetatephthalate, sucrose acetate isobutyrate, shellac, etc.) HydrophilicRelease — — — 10-65 10-40 10-40 25 — — 5 45 Modulator (e.g. HPMC, HPC,CMC, methacrylates, PLGA) Surfactant (e.g. 0-25  0-25  4-10  0-25  0-25 4-10 6 0-25  6 0-25 6 polysorbate 80, polyoxyl 40 hydrogenated castoroil, Sodium Lauryl sulfate, Sodium docusate) Processing Aids (e.g. q.s.to q.s. to q.s. to q.s. to q.s. to q.s. to q.s. to q.s. to q.s. to q.s.to q.s. to filler, binder, lubricant 100% 100% 100% 100% 100% 100% 100%100% 100% 100% 100% etc.)

TABLE IIB IN VITRO RELEASE AND PHARMACOKINETIC RESULTS OF DOSAGE FORMSDOSAGE FORM # 12 13 14 15 16 17 18 19 20 21 22 % 1 hour <10 <10 <10 <10<10 <10 6 45 1 60 <5 Progesterone 3 hours <25 <25 <25 <25 <25 <25 18 756 100 <15 Released in 6 hours ≦50 ≦50 ≦50 ≦50 ≦50 ≦50 35 100 16 100 25vitro Time to ≦12 h ≦12 h ≦12 h ≦12 h ≦12 h ≦12 h 10 h <3 h >24 h <2h >>24 h 70% release SERUM PROGESTERONE (P) PK PARAMETERS, AFTER SINGLEDOSE ADMINISTRATION (CONCENTRATIONS PER UNIT MEASURE INTICATED) P-C₂₄[ng/mL] >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 <0.2 <0.2 <0.2 <0.2 P-C_(max)[ng/mL] <10 <10 <10 <10 <10 <10 <10 >10 <10 >10 <10 C_(ave(12-24 h))[ng/mL] >0.11 >0.11 >0.11 >0.11 >0.11 >0.11 >0.11 <0.11 <0.11 <0.11<0.11

TABLE IIIA DOSAGE FORMS DOSAGE FORM # 23 24 25 26 27 28 29 30 31COMPONENT (% W/W) Progesterone 15-40 15-40 18-33 15-40 25 25 25 25  8Lipidic Lipophilic 10-50 20-50 25-50  5-30 5  5 55 5 40 Releasemodulator (e.g. carnauba waxes, hydrogenated castor oil, glyceryldistearate or combinations thereof) Hydrophilic Release — — — 15-65 35 —— 8 40 Modulator (e.g. HPMC, HPC, CMC, methacrylates, PLGA) Surfactant(e.g.  0-25  0-25  4-10  4-15 6 0-25  6 0-25 6 polysorbate 80, polyoxyl40 hydrogenated castor oil, Sodium Lauryl sulfate, Sodium docusate)Processing Aids q.s. to q.s. to q.s. to 100% q.s. to 100% q.s. to 100%q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% 100% 100%

TABLE IIIB IN VITRO RELEASE AND PHARMACOKINETIC RESULTS FOR DOSAGE FORMSDOSAGE FORM # 23 24 25 26 27 28 29 30 31 % 1 hour <10 <10 <10 <10 6 70<10 50 <10 Progesterone 3 hours <25 <25 <25 <25 18 100 15 100 <15Released in vitro 6 hours ≦50 ≦50 ≦50 ≦50 35 100 20 100 <20 Hours toT70% ≦12 h ≦12 h ≦12 h ≦12 h 9.5 h <2 h >24 h <3 h >>24 h 70%Progesterone Released SERUM PROGESTERONE (P) PK PARAMETERS, AFTER SINGLEDOSE ADMINISTRATION P-C₂₄ [ng/mL] >0.2 >0.2 >0.2 >0.2 >0.2 <0.2 <0.2<0.2 <0.2 P-C_(max) [ng/mL] <10 <10 <10 <10 <10 >10 <10 >10 <10C_(ave (12-24 h)) [ng/mL] >0.11 >0.11 >0.11 >0.11 >0.11 <0.11 <0.11<0.11 <0.11

Dosage forms 12-18 and 23-27 have levels of compositional components(progesterone, hydrophilic release modulator and surfactant, if present)that provide desired performance consistent with embodiments of theinvention. These dosage forms contain progesterone in the range of100-600 mg and can also contain an Estrogen (0.005 to 0.1 mg of ethinylestradiol, 0.05 to 5 mg of estradiol or estradiol valerate). Further,these dosage forms, when prepared without progesterone, can function asplacebo (with or without estrogen). For multi-phasic applications, thedose of progesterone and/or estrogen can be varied in the dosage form asa component of a kit.

TABLE IV DOSAGE FORMS WITH IN VITRO RELEASE AND PHARMACOKINETIC RESULTSDOSAGE FORM # 32 33 34 35 36 37 38 39 40 41 42 COMPONENT (% W/W)Progesterone 15-40 15-40 15-40 18-33 18-33 18-33 25 25 25 18-33 18-33Estrogen (Ethinyl 0.01-0.03 — — 0.015-0.025 — — 0.02 — — 0.015-0.025 —Estradiol) Estrogen (Estradiol) — 0.1-0.3 — — 0.15-0.25 — — 0.2 — —0.15-0.25 Estrogen (Estradiol — — 0.1-0.5 — — 0.25-0.35 — — 0.3 — —Valerate) Hydrophilic Release 20-80 20-65 20-65 45-65 45-65 45-65 53 5353 10-40 15-40 Modulator (e.g. HPMC, HPC, CMC, methacrylates, PLGA)Lipophilic Release 0  5-30  0-30  0-30  0-30  0-30  0-30  0-30  0-30 5-30  5-30 modulator (e.g. Ethyl cellulose cellulose acetate phthalate,sucrose acetate isobutyrate, shellac, carnauba waxes, hydrogenatedcastor oil, glyceryl distearate or combinations thereof etc.) Surfactant(e.g.  0-25  0-25  0-25  5-10  5-10  5-10 6 6 6  5-10  5-10 polysorbate80, polyoxyl 40 hydrogenated castor oil, Sodium Lauryl sulfate, Sodiumdocusate) Processing Aids (e.g. q.s. to q.s. to q.s. to q.s. to q.s. toq.s. to q.s. to q.s. to q.s. to q.s. to q.s. to filler, binder, 100%100% 100% 100% 100% 100% 100% 100% 100% 100% 100% lubricant etc.)

Dosage Form 43: Peanut Oil, Lecithin and Micronized Progesterone BasedCommercial Formulations Such as Prometrium®.

Table IV exemplifies dosage forms having 100-600 mg progesteronecombined with an estrogen (0.005 to 0.1 mg of ethinyl estradiol, 0.05 to5 mg of estradiol or estradiol valerate). Further, these dosage forms,when prepared without progesterone can function as placebo (with orwithout estrogen). For multi-phasic applications, the dose ofprogesterone and/or estrogen can be varied in the dosage form as acomponent of a kit.

Example 2 In Vitro Release of Progesterone Containing Compositions

To carry out in-vitro release of the dosage forms of the invention, adosage form according to the present invention is placed into a stirredUSP type 1 dissolution flask containing 900 mL of release mediumcomprised of DI Water dissolved with 2% w/v sodium lauryl sulfate. Inthe flasks, the dosage form is placed in a basket, so that all surfacesare exposed to the moving release media and the solutions are stirred ata rate of 100 rpm. Samples of the release medium are taken at periodicintervals. The concentration of dissolved drug in the dissolution mediumis then determined by HPLC at a UV absorbance of 245 nm using a UV-Visdetector. Drug concentration is calculated by comparing UV absorbance ofsamples to the absorbance of drug standard solutions. The mass ofdissolved drug in the dissolution medium is then calculated from theconcentration of drug in the medium and the volume of the medium, andexpressed as a percentage of the mass of drug originally present in thedosage form.

Oral dosage forms 8, 9, 11 and 43 (oil containing dosage form such ascommercial Prometrium® manufactured by Abbott Laboratories) were testedin accordance with method described above. The resulting data ispresented in the table below.

TABLE VI Dissolution data summary of few example dosage forms Dosageform Dosage form Dosage form Parameter Dosage form 8 11 09 43 %Progesterone  1 hour 6 2 80 12 Released  3 hours 19 6 100 35  6 hours 3915 100 61 22 hours 100 59 100 100 Hours to 70% T70% 10 h 26 h 0.75 h 8 hProgesterone Released

As can be seen in TABLE VI, dosage forms 09 and 43 release higher levelsof progesterone, while oral dosage form 11 is provides an excessivelyslow release rate in contrast to the desirable progesterone releaseprofile exhibited by the oral dosage form 8. FIG. 4 shows thecomparative dissolution profiles of these four oral dosage forms.

Example 3 Pharmacokinetic Testing of Progesterone Containing Oral DosageForms

Oral dosage forms 8, 9, 11 and 43 are administered to subjects in anopen-label, randomized, single-dose, crossover study performed on 16healthy volunteers. A total of 16 subjects complete the clinical phaseof the study. In each period, subjects are housed from at least 20 hoursbefore dosing until after the 24-hour blood draw. There is a 7-daywashout between each dosing period. During the study the subjects aremonitored for side effects like dizziness, drowsiness and sedation. Theplasma progesterone analysis is carried out using LC-MS/MS method.Analysis of pregnane metabolites is also carried out by validatedLC-MS/MS method. The C_(max), T_(max), AUC_(0-t) and AUC_(0-∞) arecalculated for progesterone in the plasma of the test subjects.Pharmacokinetic and statistical analyses are performed on the dataobtained from the subjects. This data, in part, is contained in thefollowing tables. The pharmacokinetic parameters are defined as follows:

-   -   AUC_(0-t): The area under the plasma concentration versus time        curve, from time 0 to the last measurable concentration of the        administered drug, as calculated by the linear trapezoidal        method.    -   AUC (AUC_(0-∞)), AUC_(inf): The area under the plasma        concentration versus time curve from time 0 to infinity. AUC was        calculated as the sum of the AUC_(0-t) plus the ratio of the        last measurable plasma concentration of the administered drug to        the elimination rate constant.    -   C_(max): The maximum measured plasma concentration of the        administered drug.    -   T_(max): The time at which the maximum measured plasma        concentration of the administered drug is achieved.    -   C_(ave(T1-T2)): The average plasma concentration of the analyte        as determined by the ratio of AUC_((T1-T2)/t) wherein “t” is the        corresponding time interval.    -   Mean: Average value of measured parameter of all individual        subjects.    -   AUC₁₂₋₂₄: The area under the plasma concentration versus time        curve from time 12 hours post dose to time 24 hours post dose.    -   P-C₂₄: Concentration of Progesterone at 24 hours after the        administration of progesterone containing oral dosage form    -   P-C₃₆: Concentration of Progesterone at 36 hours after the        administration of progesterone containing oral dosage form        The data from the analysis is given in Table VII.

TABLE VII Pharmacokinetic Data of Single Dose Cross over PK Study inhealthy volunteers DOSAGE FORM # Units 8 9 11 43 SERUM PROGESTERONE (P)PK PARAMETERS, AFTER SINGLE DOSE P-C₂₄ ng/mL 0.32 0 0.11 0.15 P-C₃₆ng/mL 0.24 0 0.08 0.11 P-C_(max) ng/mL 0.46 3.81 0.15 2.09 P-C_(max) toC₂₄ — 1.44 >10 1.44 14.27 P-AUC₁₂₋₂₄ ng * h/mL 4.49 0.41 1.48 2.16P-dose/C₂₄ mg/ 628 >1000 1903 1364 (ng/mL) TOTAL PREGNANE (PG)METABOLITES PG-C_(max) ng/mL 3.03 28.38 1.0 18.19 P-dose/PG-C_(max) mg/66 7 200 11 (ng/mL) PG-C_(ave(0-24)) ng/mL 1.75 4.69 0.45 4.03 TOTALALLOPREGNANOLONE (AP) AP-C_(max) ng/mL 1.59 17.69 0.12 11.54AP-C_(ave(0-24)) ng/mL 0.83 2.94 0.22 2.23 AP-C_(max) to P-C₂₄ —6.12 >20 24.55 114.81 Ratio P-dose/AP-C_(max) mg/ 126 11 381 17 (ng/mL)

As can be seen, oral dosage forms 9, 11 and 43 lead to either high (9 &43) or very low (11) progesterone C_(max) values along with unsuitablelevels of metabolites (9 & 43). While oral dosage form 8 providessuitable C_(max) and C₂₄ values for both progesterone and metabolites soas to enable contraception, while minimizing the metabolites and relatedside effects.

Example 4 Steady State Simulation Following Single Dose to a FemaleSubject

Simulated steady state data for single dose administration of variousprogesterone-containing oral dosage forms are prepared. FIG. 1 shows thecomparative simulated steady state plasma progesterone concentrationversus time profiles for a 400 mg progesterone dose with the Oral dosageforms 8, 11 and 43, following once daily administration. FIG. 2 showsthe comparative total progesterone metabolites concentration profilesfor the corresponding oral dosage forms. The simulated steady stateplasma progesterone levels even after a “missed dose” is shown in FIG.3, with the dose scheduled to be administered at 96 hours being delayedby 12 hours and being administered at 108 hours. As can be seen from theaccompanying figures, the plasma progesterone levels and metaboliteslevels are consistently within the therapeutic and safety range for oraldosage form 8. Even when the dosage administration is delayed for 12hours (“missed does”), oral dosage form 8 maintains the plasmaprogesterone level in the therapeutic range.

It is to be understood that the above-described various types ofcompositions, dosage forms and/or modes of applications are onlyillustrative of preferred embodiments of the present invention. Numerousmodifications and alternative arrangements may be devised by thoseskilled in the art without departing from the spirit and scope of thepresent invention and the appended claims are intended to cover suchmodifications and arrangements. Thus, while the present invention hasbeen described above with particularity and detail in connection withwhat is presently deemed to be the most practical and preferredembodiments of the invention, it will be apparent to those of ordinaryskill in the art that variations including, but not limited to,variations in size, materials, shape, form, function and manner ofoperation, assembly and use may be made without departing from theprinciples and concepts set forth herein.

What is claimed is:
 1. An oral dosage form, for ongoing administrationcomprising: an amount of progesterone; and a pharmaceutically acceptablecarrier; wherein upon single dose administration to a non-pregnant womanin follicular phase the oral dosage form provides a serum progesteroneC_(24h) of at least 0.20 ng/mL.
 2. The oral dosage form of claim 1,wherein upon single dose administration to a subject the oral dosageform provides a serum total pregnane C_(max) of no greater than 40ng/mL.
 3. The oral dosage form of claim 1, wherein upon single doseadministration to a subject the oral dosage form provides a serumprogesterone C_(max) of no greater than 10 ng/mL.
 4. The oral dosageform of claim 1, wherein upon single dose administration to a subjectthe oral dosage form provides a serum progesterone C_(24h) of 1.5 ng/mLor less.
 5. The oral dosage form of claim 1, wherein the oral dosageform has an in vitro release rate such that, when measured using a USPType-1 dissolution apparatus in 900 mL of de-ionized water with 2.0%(w/v) of sodium lauryl sulfate at 100 rpm, about 10 wt % or less of theprogesterone in the oral dosage form is released in the first 60 minutesand at least 70 wt % of the progesterone is released from the oraldosage form within 12 hours.
 6. The oral dosage form of claim 1, whereinthe progesterone is present in the oral dosage form in an amount ofabout 200 mg to about 600 mg.
 7. The oral dosage form of claim 1,wherein the progesterone is present in the oral dosage form in an amountof about 400 mg.
 8. The oral dosage form of claim 1, wherein theprogesterone comprises about 15 wt % to about 45 wt % of the oral dosageform.
 9. The oral dosage form of claim 1, wherein upon single doseadministration to a subject the oral dosage form provides a serumprogesterone AUC_(12-24h) (ng*h/mL) to administered progesterone dose(mg) ratio of at least 0.005 (ng*h/ml)/mg.
 10. The oral dosage form ofclaim 1, wherein upon single dose administration to a subject the oraldosage form provides a ratio of administered progesterone dose (mg) toserum progesterone C_(24h) (ng/mL) of about 100 mg/(ng/mL) to about 1000mg/(ng/mL).
 11. The oral dosage form of claim 1, wherein the oral dosageform further includes a pharmaceutical hydrophilic release ratemodulator present in an amount of from about 20 wt % to about 80 wt % ofthe dosage form.
 12. The oral dosage form of claim 1, wherein the oraldosage form further includes a lipophilic release modulator present inan amount of about 8 wt % to about 50 wt % of the oral dosage form. 13.The oral dosage form of claim 12, wherein the lipophilic releasemodulator is non-lipidic release modulator and is present in an amountof about 8 wt % to about 35 wt % of the oral dosage form.
 14. The oraldosage form of claim 12, wherein the lipophilic release modulator is alipidic release modulator present in the amount of about 10 wt % toabout 50 wt % of the oral dosage form.
 15. The oral dosage form of claim1, wherein the oral dosage form further includes hydrophilic releasemodulator in an amount of about 10 wt % to about 65 wt % and alipophilic release modulator present in the amount of about 5 wt % toabout 30 wt % of the oral dosage form.
 16. The oral dosage form of claim1, wherein the oral dosage form is formulated for administration to asubject to provide contraception.
 17. The oral dose form of claim 1,wherein the amount of the pharmaceutical acceptable carrier comprisesfrom about 55 wt % to about 85 wt % of the oral dosage form.
 18. Theoral dosage form of claim 1, further comprising an estrogenic agent. 19.The oral dosage form of claim 18, wherein the estrogenic agent isselected from the group consisting of estradiol, conjugated estradiol,conjugated equine estrogens, and esterified estradiol.
 20. The oraldosage form of claim 18, wherein the estrogenic agent is estradiol andis present in the oral dosage form in an amount of about 0.5 mg to about2.5 mg.